Plaque complement activation and cognitive loss in Alzheimer’s disease. J Neuroinflammation 5:9

Neurology Research Laboratory, William Beaumont Hospital Research Institute, Royal Oak, MI 48073, USA.
Journal of Neuroinflammation (Impact Factor: 5.41). 03/2008; 5(1):9. DOI: 10.1186/1742-2094-5-9
Source: PubMed


Complement activation is increased in Alzheimer's disease (AD), but its significance is unclear. The objective of this study was to determine the relationship between complement activation and cognition during the development of AD.
iC3b, C9, Bielschowsky, and Gallyas staining was performed on aged normal (n = 17), mild cognitively impaired (n = 12), and AD (n = 17-18) inferior temporal gyrus specimens. Plaques were counted in 10x fields with high numbers of Bielschowsky-stained plaques. One-way ANOVA was used to determine between-group differences for plaque counts and measures of cognitive function, and linear regression was used to evaluate global cognition as a function of Bielschowsky-stained plaques. Terms for iC3b- and C9-stained plaques were then added sequentially as additional predictors in a "mediation analysis" model.
Complement was detected on plaques in all groups, and on neurofibrillary tangles only in AD specimens. iC3b, C9, and Bielschowsky-stained plaque counts increased 2.5- to 3-fold in AD vs. other groups (all p < or = 0.01). C9 staining was present on some diffuse plaques, as well as on neuritic plaques. Bielschowsky-stained and complement-stained plaque counts were highly correlated, and were negatively correlated with cognitive measures. When the Bielschowsky plaque count was used as a predictor, its correlations with cognitive measures were statistically significant, but when iC3b and C9 plaque counts were added as additional predictors, these correlations were no longer significant. This loss of significance was attributed to multicollinearity, i.e., high correlations between Bielschowsky-stained and complement-stained plaque counts.
Both early-stage (iC3b) and late-stage (C9) complement activation occurs on neocortical plaques in subjects across the cognitive spectrum; contrary to previous reports, C9 is present on some diffuse plaques. Because of high correlations between complement-stained and Bielschowsky-stained plaque counts, quantitative assessment of the extent to which complement activation may mediate the relationship between plaques and cognitive function could not be performed. Additional studies with animal models of AD (if late-stage complement activation can be demonstrated), or possibly a trial in AD patients with an inhibitor of late-stage complement activation, may be necessary to determine the significance of this process in AD.

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    • "The significance of the complement activation in AD is not only the pathological changes in the terminal stage of AD but also reflects the early alternation in the disease course, i.e. mild cognitive impairment (MCI). For example, Loeffler et al. [58] have performed studies on iC3b, C9, Bielschowsky and Gallyas staining in in brains with 18 AD, 12 MCI with that from 17 aged normal controls and identified iC3b, C9, and Bielschowsky-stained plaque counts increased 2.5- to 3-fold in AD compared to MCI and control subjects. C9 staining was present on some diffuse plaques, as well as on neuritic plaques. "
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    ABSTRACT: Increasing evidence suggests that inflammatory and immune components in brain are important in Alzheimer's disease (AD) and anti-inflammatory and immunotherapeutic approaches may be amenable to AD treatment. It is known that complement activation occurs in the brain of patients with AD, and contributes to a local inflammatory state development which is correlated with cognitive impairment. In addition to the complement's critical role in the innate immune system recognizing and killing, or targeting for destruction, complement proteins can also interact with cell surface receptors to promote a local inflammatory response and contributes to the protection and healing of the host. On the other hand, complement activation also causes inflammation and cell damage as an essential immune function to eliminate cell debris and potentially toxic protein aggregates. It is the balance of these seemingly competing events that influences the ultimate state of neuronal function. Our mini review will be focusing on the unique molecular interactions happening in the AD development, the functional outcomes of those interactions, as well as the contribution of each element to AD.
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    • "At present, it is widely discussed that AMD shares common pathological hallmarks with Alzheimer's disease (AD) (Chiu et al. 2012; Dasari et al. 2011; Dentchev et al. 2003; Kaarniranta et al. 2011; Ohno- Matsui 2011; Yoshida et al. 2005). Like AD, AMD is characterized by Ab deposition and associated with changes in complement factors and ApoE (Laws et al. 2003; Loeffler et al. 2008). Oxidative stress and inflammation are strongly linked to pathogenesis of both diseases (Kaarniranta et al. 2011). "
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    • "Further cleavage of C3b results in smaller fragments designated iC3b, C3c and C3d, which may serve other unknown functions (Nishida et al., 2006). As with C1q, C3b and its cleavage product iC3b have been found deposited on AD-affected neurons (Loeffler et al., 2008), which would facilitate efficient removal by microglia. Although the activation of C1q in AD described above seems to have detrimental effects on CNS homeostasis, the story of C3 activation seems more complicated and may only function properly within specific ranges. "
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